Connectivity in the human and the monkey brain probes causal involvement of the fornix in Mild Cognitive Impairment and Alzheimer’s Disease

Abstract Alzheimer’s disease (AD) is characterised by memory loss and severe deficits in cognitive function associated with neural degeneration in a network of brain regions. However, little is known about those regions’ connectivity patterns and how that differs from mild cognitive impairment (MCI) or healthy aging. To address that, we used diffusion-weighted MRI to determine connectivity across 11 key memory-related regions and their unique set of connections (connectivity fingerprints) to 14 white matter (WM) tracts. One WM tract particularly important for memory, and attractive target for therapeutic interventions in AD, is the fornix. However, determining fornix-specific contributions to memory deficits or therapeutic benefits is difficult, partly because the fornix carries numerous subcortical and cortical projections. To explore that, we additionally examined MRI-derived connectivity across homologous structures in non-human primates before and after fornix transections. We report several important findings. First, that connectivity between the hippocampus and the anterior thalamus (ATh) is strongly compromised in cognitive decline, as is fornix integrity. We also found strong reductions in the hippocampus-fornix and ATh-fornix connectivity in AD, demonstrating that fingerprint divergence across groups in hippocampal CA1 and ATh can identify differences between people with AD and MCI. In AD, we observed also elevated connectivity between WM tracts and the hippocampus or the ATh, suggesting a compensatory mechanism, which, importantly, depends on a viable fornix. We finally demonstrate that certain thalamic nuclei and hippocampal subfields link through the retrosplenial cortex in both species, highlighting its potential role as an alternative target for interventions in memory disorders. Competing Interest Statement The authors have declared no competing interest. Footnotes ↵* Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf